Prevention of Neural Tube Defects in Europe: A Public Health Failure.

Objective: Thirty years ago it was demonstrated that folic acid taken before pregnancy and in early pregnancy reduced the risk of a neural tube defect (NTD). Despite Public Health Initiatives across Europe recommending that women take 0.4 mg folic acid before becoming pregnant and during the first trimester, the prevalence of NTD pregnancies has not materially decreased in the EU since 1998, in contrast to the dramatic fall observed in the USA. This study aimed to estimate the number of NTD pregnancies that would have been prevented if flour had been fortified with folic acid in Europe from 1998 as it had been in the USA. Design and Setting: The number of NTD pregnancies from 1998 to 2017 that would have been prevented if folic acid fortification had been implemented in the 28 countries who were members of the European Union in 2019 was predicted was predicted using data on NTD prevalence from 35 EUROCAT congenital anomaly registries and literature searches for population serum folate levels and folic acid supplementation. Results: From 1998 to 2017 an estimated 95,213 NTD pregnancies occurred amongst 104 million births in the 28 countries in the EU, a prevalence of 0.92 per 1,000 births. The median serum folate level in Europe over this time period was estimated to be 14.1 µg/L. There is a lack of information about women taking folic acid supplements before becoming pregnant and during the first trimester of pregnancy, with one meta-analysis indicating that around 25% of women did so. An estimated 14,600 NTD pregnancies may have been prevented if the European countries had implemented fortification at the level adopted by the USA in 1998 and 25% of women took folic acid supplements. An estimated 19,500 NTD pregnancies would have been prevented if no women took folic acid supplements. Conclusions: This study suggests that failure to implement mandatory folic acid fortification in the 28 European countries has caused, and continues to cause, neural tube defects to occur in almost 1,000 pregnancies every year.

Maternal risk associated with the VACTERL association: A case-control study.

BACKGROUND: The VACTERL association (VACTERL) includes at least three of these congenital anomalies: vertebral, anal, cardiac, trachea-esophageal, renal, and limb anomalies. Assisted reproductive techniques (ART), pregestational diabetes mellitus, and chronic lower obstructive pulmonary disorders (CLOPD) have been associated with VACTERL. We aimed to replicate these findings and were interested in additional maternal risk factors. METHODS: A case-control study using self-administered questionnaires was performed including 142 VACTERL cases and 2,135 population-based healthy controls. Multivariable logistic regression analyses were performed to estimate confounder adjusted odds ratios (aOR) and 95% confidence intervals (95%CI). RESULTS: Parents who used invasive ART had an increased risk of VACTERL in offspring (aOR 4.4 [95%CI 2.1-8.8]), whereas the increased risk for mothers with CLOPD could not be replicated. None of the case mothers had pregestational diabetes mellitus. Primiparity (1.5 [1.1-2.1]) and maternal pregestational overweight and obesity (1.8 [1.2-2.8] and 1.8 [1.0-3.4]) were associated with VACTERL. Consistent folic acid supplement use during the advised periconceptional period may reduce the risk of VACTERL (0.5 [0.3-1.0]). Maternal smoking resulted in an almost twofold increased risk of VACTERL. CONCLUSION: We identified invasive ART, primiparity, pregestational overweight and obesity, lack of folic acid supplement use, and smoking as risk factors for VACTERL.

Prevention of congenital malformations and other adverse pregnancy outcomes with 4.0 mg of folic acid: community-based randomized clinical trial in Italy and the Netherlands.

BACKGROUND: In 2010 a Cochrane review confirmed that folic acid (FA) supplementation prevents the first- and second-time occurrence of neural tube defects (NTDs). At present some evidence from observational studies supports the hypothesis that FA supplementation can reduce the risk of all congenital malformations (CMs) or the risk of a specific and selected group of them, namely cardiac defects and oral clefts. Furthermore, the effects on the prevention of prematurity, foetal growth retardation and pre-eclampsia are unclear.Although the most common recommendation is to take 0.4 mg/day, the problem of the most appropriate dose of FA is still open.The aim of this project is to assess the effect a higher dose of peri-conceptional FA supplementation on reducing the occurrence of all CMs. Other aims include the promotion of pre-conceptional counselling, comparing rates of selected CMs, miscarriage, pre-eclampsia, preterm birth, small for gestational age, abruptio placentae. METHODS/DESIGN: This project is a joint effort by research groups in Italy and the Netherlands. Women of childbearing age, who intend to become pregnant within 12 months are eligible for the studies. Women are randomly assigned to receive 4 mg of FA (treatment in study) or 0.4 mg of FA (referent treatment) daily. Information on pregnancy outcomes are derived from women-and-physician information.We foresee to analyze the data considering all the adverse outcomes of pregnancy taken together in a global end point (e.g.: CMs, miscarriage, pre-eclampsia, preterm birth, small for gestational age). A total of about 1,000 pregnancies need to be evaluated to detect an absolute reduction of the frequency of 8%. Since the sample size needed for studying outcomes separately is large, this project also promotes an international prospective meta-analysis. DISCUSSION: The rationale of these randomized clinical trials (RCTs) is the hypothesis that a higher intake of FA is related to a higher risk reduction of NTDs, other CMs and other adverse pregnancy outcomes. Our hope is that these trials will act as catalysers, and lead to other large RCTs studying the effects of this supplementation on CMs and other infant and maternal outcomes. TRIAL REGISTRATION: Italian trial: ClinicalTrials.gov Identifier: NCT01244347.Dutch trial: Dutch Trial Register ID: NTR3161.

Maternal high-dose folic acid during pregnancy and asthma medication in the offspring.

PURPOSE: Low-dose folic acid supplementation (0.5 mg) taken during pregnancy has been associated with an increased risk for childhood asthma. The effect of high-dose folic acid (5 mg) advised to women at risk for having a child with neural tube defect has not been assessed so far. Our aim was to investigate the effect of dispensed high-dose folic acid during pregnancy and asthma medication in the offspring. METHODS: We used data from the pregnancy database IADB.nl, which contains pharmacy-dispensing data of mothers and children from community pharmacies in the Netherlands from 1994 until 2011. The dispension of asthma medication in children exposed in utero to high-dose folic acid was compared with children who were not exposed to this high dose. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were calculated. RESULTS: In 2.9% (N = 913) of the 39,602 pregnancies in the database, the mother was dispensed high-dose folic acid. Maternal high-dose folic acid was associated with an increased rate of asthma medication among children: recurrent asthma medication IRR = 1.14 (95%CI: 1.04-1.30) and recurrent inhaled corticosteroids IRR = 1.26 (95%CI: 1.07-1.47). Associations were clustered on the mother and adjusted for maternal age, maternal asthma medication, and dispension of benzodiazepines during pregnancy. CONCLUSION: Almost 3% of the children were prenatally exposed to high-dose folic acid. This study suggests that supplementation of high-dose folic acid during pregnancy might increase the risk of childhood asthma.

Periconceptional folic acid associated with an increased risk of oral clefts relative to non-folate related malformations in the Northern Netherlands: a population based case-control study.

Periconceptional folic acid has been associated with a reduced risk of neural tube defects, but findings on its effect in oral clefts are largely inconclusive. This case-control study assesses the effects of periconceptional folic acid on cleft risk, using complementary data from the Dutch Oral Cleft Registry and a population-based birth defects registry (Eurocat) of children and foetuses born in the Northern Netherlands between 1997 and 2009. Cases were live-born infants with non-syndromic clefts (n = 367) and controls were infants or foetuses with chromosomal/syndromal (n = 924) or non-folate related anomalies (n = 2,021). We analyzed type/timing/duration of supplement use related to traditional cleft categories as well as to their timing (early/late embryonic periods) and underlying embryological processes (fusion/differentiation defects). Consistent supplement use during the aetiologically relevant period (weeks 0-12 postconception) was associated with an increased risk of clefts (adjusted odds ratio 1.72, 95% confidence interval 1.19-2.49), especially of cleft lip/alveolus (3.16, 1.69-5.91). Further analysis systematically showed twofold to threefold increased risks for late differentiation defects-mainly clefts of the lip/alveolus-with no significant associations for early/late fusion defects. Effects were attributable to folic acid and not to other multivitamin components, and inclusion of partial use (not covering the complete aetiologically relevant period) generally weakened associations. In conclusion, this study presents several lines of evidence indicating that periconceptional folic acid in the Northern Netherlands is associated with an increased risk of clefts, in particular of cleft lip/alveolus. This association is strengthened by the specificity, consistency, systematic pattern, and duration of exposure-response relationship of our findings, underlining the need to evaluate public health strategies regarding folic acid and to further investigate potential adverse effects.

Protective effect of periconceptional folic acid supplements on the risk of congenital heart defects: a registry-based case-control study in the northern Netherlands.

AIMS: To investigate the potentially protective of periconceptional folic acid use on the risk of congenital heart defects (CHDs) relative to other non-folate related malformations. METHODS AND RESULTS: We analysed data from a large regional register of birth defects (EUROCAT-Northern Netherlands), over a 10 year period (1996-2005) for a case-control study. The cases were mothers who had delivered infants with isolated or complex heart defects, without any related syndrome or genetic abnormality (n = 611). We used two control groups; one from the EUROCAT database and another from the general population. The registry controls consisted of mothers of children with a known chromosomal or genetic defect, and with infants with other non-folate related congenital malformations (n = 2401). Additional folic acid was taken as a single supplement or as a multivitamin containing folic acid in a dose of >or=400 microg daily. Mothers who had used folate antagonists or who had diabetes, and mothers of children with oral clefts, hypospadias, limb reduction- or neural tube defects, were excluded from both groups. Potentially confounding factors of periconceptional folic acid use in relation to CHD were explored, including baby's birth year, maternal body mass index, education, maternal age at delivery of index baby, smoking behaviour, and alcohol use during pregnancy. Periconceptional folic acid use revealed an odds ratio (OR) of 0.82 (95% CI 0.68-0.98) for all types of CHD relative to other malformations. The estimated relative risk for CHDs of additional folic acid use compared with the general population was comparable [OR 0.74 (95%CI 0.62-0.88)]. Subgroup analysis showed an OR of 0.62 (95% CI 0.47-0.82) for isolated septal defects. The proportions of the potential confounders between mothers of case and control infants did not differ significantly. CONCLUSION: Our results support the hypothesis that additional periconceptional folic acid use reduces CHD risk in infants. Use of periconceptional folic acid supplements was related to approximately 20% reduction in the prevalence of any CHD. Given the relatively high prevalence of CHD worldwide, our findings are important for public health.

Ten years after the Dutch public health campaign on folic acid: the continuing challenge.

BACKGROUND: Folic acid use in the periconceptional period reduces the risk of neural tube defects (NTDs). However, applying this knowledge in daily practice is not an easy task. We report here the current level of folic acid use in the Netherlands and discuss the figures within the framework of a national governmental campaign held in 1995 promoting the use of folic acid and the professional interventions undertaken since then. METHODS: We carried out six studies in the northern Netherlands during 1995, 1996, 1998, 2000, 2003 and 2005, respectively. The same methodology in the same health professionals' practices was followed in all studies. Pregnant women attending their first or second antenatal visit were asked to fill in a questionnaire aimed at assessing their awareness and use of folic acid. RESULTS: In 2005, most of the pregnant women used folic acid "at some time in their pregnancy", and 51% used it for the entire advised period. Prior knowledge on the protective affect of folic acid and on the period of use was strongly related to the level of education. The use of folic acid in a previous pregnancy [odds ratio (OR) 3.9, 95% confidence interval (95% CI) 1.6-9.9], the use of an oral contraceptive (OR 2.1, 95% CI 1.1-4.1) and parity (OR 0.08, 95% CI 0.01-0.5) significantly predicted the current correct use. The most recent figures revealed that there is still a large gap between more highly and less educated women in terms of taking folic acid in the advised period: 63 versus 31%, respectively. DISCUSSION: The aim of the Dutch Ministry of Health is to have 70% of Dutch women wanting to become pregnant use folic acid supplements in the advised period by 2010. While this level has almost been reached among more highly educated women (63%), it will take a great deal more effort, money and creativity to achieve the necessary increase from the current level of 31% among women with a lower educational background.

Folic acid sensitive birth defects in association with intrauterine exposure to folic acid antagonists.

Since the protective effect of folic acid (FA) on birth defects is well known, it is reasonable to assume intrauterine exposure to FA antagonists increases the risk on these defects. We have therefore performed case-control analyses to investigate the risk of intrauterine exposure to FA antagonists, using data on births from the EUROCAT Northern Netherlands registry from 1997 to 2002. Of the 815 cases, 11 were exposed to a FA antagonist compared to 16 of the 1402 controls. For FA sensitive defects as a group, the study showed no effect after exposure to a FA antagonist (odds ratio (OR)=1.18, 95% CI: 0.55-2.57). We found no effect after exposure to a dihydrofolate reductase inhibitor (DHFRI) (OR 0.44, 95% CI: 0.12-1.54), but we did find a statistically significant effect after exposure to an antiepileptic drug (OR=3.45, 95% CI: 1.04-11.48). This study supports the findings of various other studies on the teratogenicity of antiepileptics. An association between DHFRIs and FA sensitive defects was not found.

Influence of educational level on determinants of folic acid use.

In The Netherlands, periconceptional folic acid use to prevent neural tube defects was promoted through a national 'Folic Acid Campaign'. In two regions, a local campaign supplemented the national campaign to increase the chances of reaching women with low socio-economic status (SES). A framework of outcome criteria, defined as awareness knowledge, perceived safety, attitudes and subjective norms, was developed to evaluate the effectiveness of the two local campaigns. Data were gathered by means of two cross-sectional studies conducted just before and 1 year after the campaigns took place. Before the campaigns were conducted, there were already differences in all effect criteria and folic acid use between women of different educational levels, mostly in favour of women with a high level of education. Although both educational campaigns appeared to have a positive impact on all outcome criteria, they failed to reduce the existing differences in these outcome criteria between women of different educational levels. Folic acid use can be promoted effectively by mass media campaigns, certainly in a large group of women with no prior knowledge of the health benefits associated with periconceptional folic acid use. However, in order to achieve more equal health outcomes among women of low and high SES, it seems that more tailored interventions for women of low SES are needed.